Diphenyl ethers and process of preparing same



l Patented Apr. 8, 1952 DIPHENYL EfrHER's iiNDl PROCESS- or* PREPARINGEdward 'feggin orrows, London, Eng-land, as-

Signor to Glaxo Laboratories Limited, Greenford, England, a'. Britishc'liy Ne Drawingl Application: April 24, 195o, serial. Ne. 157,855. in'Great Brita-in october 23, 194':

v I y This invention which is a Acontinuation-iri-part of the inventionHdescribed in vmy application Serial No.' 54,585 filed October 14;-1948; is con cer'ne'd with improvements in or relating tothe preparationof diphenyl ethers" of the general formula NO: X l v .c

its;

(Where is a ltertiary base which may be aliphatic, partly aromatia orone in which the nitrogen is part ofa heterocyclic ring, R is Yany`substituent suchl as Will not interfere with the reaction andpreferablyr a. group readily convertible to an alanine side chain and Xis a suitable anion as hereinafter deh-ned?,- w-ith a -phenol of thegeneral form-ula*r Where R is a group such as will not interfere withthe reaction.- y

l I1? shuldbe noted that they new products' btinect wher-1f R isf Va-ygfroufp readily convertible intoalanine side chain4 and R1 a hydroieygFi-"oiip` or at groupr'eadily convertible thereto 'are valuable inlthev synthesis of. thyroxine'.

The terma suitable anion?" asil used herein iheanthe--ariionic portionof an aryl` s'ulphonic acidi or' of hydrochloric@ acid., hydrobromicacid yor hydriodic'l acid.` Y

i According to the invention therefore'jtheref is provideda process forthe preparation of diphenyl others offtheftype specified in" Whclra'fqiiatei-nary i salt' of general formula:

Y Y c N102 is reacted with a phenol of general formula 5 Y WHI'fel` RN,R', R arid X have the meanings stated herein. l

It has been found that in order that the diphenyl ethers of" the abovegeneral formula may be useful ithe synthesis of thyroiiine, it ispreferable that the group Rf should be one .of the' fol-lowing' grouls:l

-onzonfico'oz cHr-oH-oo' ee -oiizonoooz NH NH i NHY o0 Where Z is analkyl g'ioiil'ocontainingnot' iore than four' e'arlon atons and Y is` anacyl group, such as an acetyl group of a berlzoyl group. These vgifolipsare all convertible by the' us'al methods iritov an alanine side chain.

For similar reasons it has heen found further, that it is preferablethat R should be a hydroxyl group, a hydroxyl group protected by agr'oup sov remevtl'e therefrom such as a methyl, ethy1 or acetyl groupor an` amino groi'ip' protected hy l an' eyi greep sueiii as acetyl,prepinoyicr benzjyl group;

While the pro'c'essaccor'ding t'o' theinvention rfeadilycarri'ed otrithe absence of a solvent, it has been fdn'd that'gen'ally the" presenceof :a suitable. solvent is" preferable. The choice'of solvent is' adielectric constant less than' 25 is found to? vbe satisfactory.Examples of such' solvents' vare liquid sulphur" dioxide, liquidamln'onia and inenzeie,v or" an excess;v of the tertiaryL base 'ch for'exaiple' a's" an excess of' pyridine.

At: prsent it' hasv been foiirid that it is prefera'ble" that'thesuitable' anion should' be" the anion of p'-to'lu`ene` sulphonic afci'd.l. .f

Eiample's' of the suitab e tertiary base RN' are pyridine; de'thylanlne,the pi'cblies, dimethyl- According to a still further feature of theinvention it has been found that in many cases Where the'suitabl'e anionisjthe anion of anaryl sulphonio acid it is not necessary to preprepareand/or isolate the quaternary salt or even the ester' from which it: istriorimally` prepared as the'- reaetioriof the" present invention cani becovenietlyc'arriedoieprovided that the several components for" forming"these sustancesare present the proper proportions`. This method ef'procedure isf illustrated-f in-1 Example 4". e.

somewhat dicult but a solvent having to prepare compounds in which R" isa hydroxyl, methoxy or acetoxy group and the invention accordinglyspecifically includes the preparation of such compounds.

It has been found further that where the group R is -CHZCHo o oz NHYwhich contains an optically active carbon atom, the use of the opticallyactive dinitrophenol in the process according to the invention yields anoptically active dinitrodiphenyl ether. Thus for example if a laevocompound is used, a laevo product is obtained. The production ofoptically active isomers in this way is of use in the synthesis ofL-thyroxine which compound has greater physiological activity thanracemic thyroxlne. The invention therefore includes the use of opticallyactive starting materials Where the group R' is oHzCHooz NHY In orderthat the invention may be well understood the following examples aregiven only as illustrations:

EXAMPLE 1 Preparation of 3:5-dinitro-4-(4'-hydroy ormethoy-phenoy)benzylhydantoin (a) Preparation of tosylester.-3:5dinitro4 hydroxy benzyl hydantoin (10 parts) was heated inwater (100 parts) containing p-toluenesulphonyl chloride (6.4 parts) ona steam bath, and sodium carbonate (1.8 parts) was added in smallportions. When half the latter had been added a white solid began toseparate out. Heating was continued for two hours, the reaction mixturewas cooled and the solid product filtered 01T and dried. The product onrecrystallisation from aqueous alcohol yielded the tosyl ester. (70%) M.P. 208.

(b) Condensation with hydroquz'none.-The above tosyl ester (l part) andhydroquinone (1 part) in pyridine (l parts) was heatedV under reflux for1 hour. The solution was evaporated in vacuo to dryness and the residueextracted with hot acetic acid. The ltered acetic acid solution aftertreatment with charcoal, was diluted with water when 3:5-dinitro-4-(4hydroxyphenoxy) -benzyl hydantoin separated as yellow prisms. (49%) M. P.242. Found C, 49.7, H, 3.4; N,.14.1%; CieHmOraNi'requiresC, 49.5; I-I,

Preparation of ethyl 3:5-dz'nz'tro-4(4methoxy phenoy)dihydrocinnamate l(a)P1eparation of tosyl derivative.-Ethyl3:5dinitro-4-hydroxy-dihydrocinnamate (7.1 parts) and diethylaniline (20parts) were treated with toluenesulphonyl chloride (6 parts) on thesteam bath for four hoursduring which time a red homogeneoussolution-was formed. The mixture was washed with dilute hydrochloric-racid and` ethyl alcohol and the product crystallised from aqueous aceticacid to yield the tosyl derivative. (63%) M. P. 102.

(b) Condensation with quinolmonomethyl athen-The tosyl derivative (22parts) and quinolmonomethyl ether (20 parts) were refluxed in pyridinesolution for one hour. The hot solution Was diluted with water and alittle alcohol and the deposited solid filtered and recrystallised frommethyl alcohol. M. P. 102.

(c) Preparation of the pyridinium quaternary salt from the tosylesten-The tosyl ester (44 parts) in pyridine (200 parts) was heated forten minutes and the product precipitated with ether; the quaternarycompound was crystallised from a mixture of ethyl alcohol/ether. (89%)M. P. 172.

(d) Condensation of the quaternary salt with. quinolmonomethyl einen-Thequaternary salt (25 parts) was dissolved in liquid ammonia (2000 parts)to which quinol monomethyl ether (20 parts) was added rapidly. Thesolvent was allowed to evaporate 01T during about three hours and theresidue crystallised from ethyl alcohol giving ethyl 3 -dinitro-l-(4-methoxyphenoxy) dihydrocinnamate. (97%) M. P. 100. Recrystallisationfrom ethyl alcohol raised the M. P. to 102.

(e) Preparation of ethyl 3:5-dinnro-4-pyr- Preparation of 35-dz'nz'tro-4- (4metho:cyphen oxy) -toluene (a)3:5-dinitro-4-tosyloxy-toluene (35 parts) was treated in liquid SO2 forthree hours with pyridine (24 parts) and quinolmonomethyl ether (40parts). After removal of SO2 by evaporation the residue was crystallisedfrom alcohol to give 3:5 dinitro-4-(4-methoxyphenoxy) toluene. (12%) M.P. 146.

(b) 4-bromo-3:-dinitrotoluene (5 parts) was dissolved in pyridine (50parts) to form the quaternary compound and the solution was refluxedwith quinolmonomethyl ether (5 parts) for one hour. The residue obtainedon evaporation of the pyridine was treated with dilute alkali to yieldthe above diphenyl ether, M. P. 142.

(c) Preparation of 3:5-dinitro-4-benzenesalphonyZoy-toZuene.-3 :5dinitro p cresol (5 parts) Was heated with water (10 parts) and sodiumcarbonate (.53 parts) till dissolved when benzene sulphonyl chloride(1.6 parts) was added slowly with stirring. After one hour theprecipitated benzene sulphonyl ester was ltered, washed with sodiumcarbonate solution and Water, and recrystallised from acetic acid asyellow plates (60%) M. P. 166.

(d) The benzene sulphonyl ester (l part), quinolmonomethyl ether (1part) and pyridine .zene v (50 pants) for two hou-rs. l removed in vacuo.and thediphenyl other isolated Y as usual (50%).

dii-phenyl ether `in (h), :(1 part) was heated in an oil 'bath phenol (4parts) at 180 for three hours. The 'cooled reaction mixture was pouredvinto l2 N alkali and the crystalline solid filtered and crys- -iromethyl alcohol giving the above ether. .(60%) P. 134.

l(l5 parte) were reuxed `for one hour. fflhe cooled solution swas pouredinto dilute sodium hyvcir-oxido .and the product which separated `wasrecrystallised from alcolici to. form pale yellow needles (94%) M. P.146.

'(e) The preparation was carried out` exactlyy as (d.) usi-ng collidine.to give the diphenyl ether lo) -3 :sommo-44055110@ toluene (roert),

quinoln'lonomethyl ether (1 part)V andjdiethylaniline (10 parts) wereheated in an oil bath at 140 for six hours. The cooled solution wasdiluted with chloroform and washed `with dilute hy* drochloric acid,`water and sodium carbonate solution. The chloroform solution wasevaporated to dryness and the residue crystallised from alcohol toobtain the diphenyl ether.

i ()"13z5-di'nitro 4 toluene-suiphonyloXy-tol- "uene (2 parts),quinolmonomethylether (2 parts) (4l'emethoxyphenoxy). toluene.

(n) 'Preparation of 3:5 amico-pyridinium toluene toluenesulphonate-3-dinitro-l-tosyloxy toluene (l part) 'with dry pyridine (5 parts) Awas"heated on the steam bath for five minutes. *The mixture -Wascooled anddiluted with ether.

The solid which separated was filtered and crystallised from alcohol toyield the quaternary compound as long colourless needles (70%) M. P.184. i

(i) The quaternary salt parts) Was refluxed with Aquinolmoriomethylother@ parts) in ben- The solvent was (lo) T 'he reaction carried outVasin (fi) `using ethyl acetate or amyl acetate as solvent, vgave the 30%yand `20% yields.

EXAMPLE 4 'Preparation of -3 :5-rlinz'tro-w4-phenomy toluene v(al) TheQuaternary saltprepared inExample 3 with tallised from ethylalcohol togive the diphenyl ether as yellow needles (86%) M. P. `134".

` (b) 3:5-dinitro-p-.cresol (5 parts), toluenesulphonylchloride (5parts) and pyridine (20 parts) were .heated .in an oil -bath at U-110for one hour. Phenol (20 parts) was added and the mix- Hture heated at18o-190 forth-ree hours. The

melt was. poured -into 2 N caustic soda and the precipitated solid` wasltered `and kcrystallised diphenyl EXAMPLE 5 The "Quaternary saltprepared in Example 3 (h) .6 EXAMPLE 6 Preparation of3:5-dim'tro-4(4'--nitvophe'nofcy) .crystallised from benzene/petroleumether mix'- ture M. P. 172. I

EXAMPLE v EXAMPLE 8 Preparation of 3:5-dnitro 4(4' methorypheo- Oxy)beneoate Methyl 4-chloro-3:5A-dinitrobenzoate (l part) dissolved inpyridine to form a deep red solution from which the pyridiniumQuaternary compound separated on standing. Quinolmonomethyl `eth'erwasadded to the mixture and the whole reiiuxed for 30 minutes. The vcooledsolutionwas poured into 2 N .caustic soda and the precipitated methyl-3z 5-dinitro 4(4 -methoxy-phenoxy') ben- `zoate` was filtered off andcrystallised '(50%) EXAMPLE `9 L-.3 :5-dinitro-4( 4 -methoypheno-y) N-acety/l- 1 phenylalanine ethyl ester u AL-NAcetyldinitrotyrosine 'ethylester (20 vgil mol) and p-toluenesulphonyl chloride (12.4 g,` 1.1 mols)were dissolved in dry kpyridine (100 mi.) and warmed in the steam bathuntil all the material was in solution. Quinol monomethyl ether (21.3 g.3 moles) Was added and the solution reiiuxed for one hour. The pyridinewas then removed in vacuo and theresidual oil was taken up in ethylacetate (200 ml.) and shaken with 2 N HCl (2x50 ml.) in order to'free itfrom traces of pyridine. The ethyl acetate was removed by distillationand the residual oil taken into alcohol from which it was precipitatedwith water.. 'Ilvhe precipitated oil was ltaken into boiling ethylacetate (charcoal) and precipitated 4out with petrol B. P. 60-80". Yield183g. .(70%) M. P. 1-10-l11. (Found C, 53.2; H, 4.72; N, 9.4;CzoI-IzlOsNa .requires C, 53.7; H, 4.70; N, 9.4% (c )n -22. 2.)

EXAMPLE' 1-0 L-3:5-dinitro-N-acetyltyrosine ethyl ester. (1.3 g. 1 mol)and p-toluene-sulphonyl chloride (20.75 g. 1.05 moles) were dissolyedindry pyridine :(20 mls.) by :heating to (iO- on the steam bath.`p-Acetoxyphenol (1.52 g. 2.5 moles) -was added and the vsolutionrefluxed for 1 hour. The pyridine was removed in vacuo andthe residualoil treated with boiling ethyl acetate; the majority of the material wassoluble but a black residual oil was left. The ethyl acetate wasdecanted offv and taken to dryness when a clear amber gum was obtained.This was dissolved in alcohol, yprecipitated lby addition civ water, andthen charcoaled in ethyl acetate solution .from which it N-ccctyl wasprecipitated with petroleum ether B. P. 60-80". The gum was thendissolved in acetone and passed through an alumina column; a clearyellow acetone solution was obtained and on removing the acetone bydistillation a clear gum was obtained which solidified on scratching,yield 1.05 g. (55%) M. P. 104-106". This material was recrystallisedtwice from benzene-M. P. 105-106". (Found C, 52.7; H, 4.4; N, 8.8%;C21H21O10N3 requires C, 52.8; H, 4.4; N, 8.8% (a)D-20.5.)

EXAMPLE 11 (a) MonopropionylquinoL Propionic anhydride (5.9 m1.) wasadded dropwise t a stirred cooled solution of hydroquinone g.) andsodium carbonate (1.43 g.) in water (100 ml.) to which a small amount ofsodium hydrosulphite had been added. During the reaction sodiumcarbonate solution was added to keep the solution alkaline and after twohours the precipitate was ltered off and recrystallised from petrolether as colourless needles M. P. 110 (3.25 g.)

Analysis identified it as glproponylquinol Found: C, 64.4. H, 6.1%012511404 requires: C, 64.9 H, 6.3%

The mother liquors were acidied and extracted with ether and the extractdried and as yellow prisms M. P. 150 (0.3 g.) (found C,

55.7; H, 3.9; N, 8.2 C1sH14O7N2 requires C, 55.5; H, 4.05; N, 8.1%).

EXAMPLE 12 i3 5dinitro44-acetamidop-henoytoluene 3:5-dinitro-p-cresol(2.5 g.) and p-toluene sulphonyl chloride (2.5 g. 1 mol) in pyridine (10c. c.) were heated at 110 for l/2 hour. The solution was then cooled,and p-acetamidophenol g.) was added. After having been heated at 120 for2 hours the mixture was poured into dilute caustic soda solution. Thebrown oil crystallised on scratching (3.7 g.; 89%). The pure etherseparated from alcohol as yellow needles M. P. 195 (found N, 12.6.C15H1'3O5N3 requires N, 12.7%).

EXAMPLE 13 3 5-dz'nz'tro-4- (4 acetamidopheinoxy-N-acetyl)DL-phenylalamne ethyl ester 3:5dinitro-N-acetyl-DL-tyrosne ethyl ester(16 g.) and p-toluene sulphonyl chloride (9.8 g. 1.1 mol.) in pyridine(70 c. c.) were kept at 110 for 1/ hr. p-Acetamidophenol (21 g.) 'wasthen added and the mixture boiled gently under reux for 2v hours. Thecooled solution was poured into a large Volume of dilute HC1, from whichthe product was extracted with two portions of ethyl acetate. Afterbeing washed with very dilute caustic soda solution and then Water theethyl acetate was removed by distillation. The residual oil (20 g. 90%)crystallised when seeded with some crystals of the diphenyl etherprepared -in a preliminary experiment. However, recrystallisation wasdifficult and did not give a sharply melting product. The material wastherefore redissolved in dry ethyl acetate and passed down a column ofactivated alumina. Recrystallisation of the most easily eluted fractionsfrom alcohol gave 13 g. (58%) of the diphenyl ether melting at 173-175.Repeated recrystallisation from alcohol or aqueous methanol yieldedsmall, pale yellow needles, M. P. 178 (found C, 53.2; H, 4.8; C21H2zO9N4requires C, 53.15; H, 4.6%).

EXAMPIE 14 3 5dinitro`4 4 '-acetamidophenoxy) -N -acetyl- L-phenylalamneethyl ester 3:5-dinitro-N-acetyl-L-tyrosine ethyl ester (5 g.) andbenzene-sulphonyl chloride (2.5 g.; 1.1 mol.) in pyridine (50 c. c.)were boiled for l@ hr. p-Acetamidophenol (7.5 g.) was then added andboiling continued for another hour. The product was extracted fromdilute HC1 with chloroform. The solid remaining after evaporation of thechloroform was dissolved in acetone and chromatographed on alumina toyield a pale yellow eluate, which was recrystallised from acetonitrile.A second crystallisation gave minute yellow needles (3.6 g.; 52%)beginning to soften at 110 but not completely melted till 160. They weredried in vacuo at 60 before analysis (found: C, 52.6; H, 4.5; N, 12.0.C21H22O9N4 requires C, 53.2; H, 4.7; N, 11.8%).

EXAMPLE 15 melting with elervescence at 275. A second crystallisationdid not change the M. P. (8.6 g.; 60%) (found: C, 50.4; H, 3.6; N, 16.4.CnHisOsNs requires C, 50.35; H, 3.5; N, 16.3%).

` EXAMPLE 16 Methyl 3:5 dzmtro-fl-(4benzamdophenoy) benzoateMethyl-3z5dinitro-4-chlorobenzoate (5 g.) was dissolved in dry ethylacetate c. c.) and picoline (3.5 g.; 2 mols) -was added.p-Benzamidophenol (8 g.; 2 mols) was added to the warm solution, whichwas then boiled gently for 5 hours. The solid remaining after removal ofthe solvent was washed with 2 N caustic soda, 2 N HCl and water, andrecrystallised from acetic acid. The fine yellow needles (4.5 g.; 55%)then melted at 243-245", raised to 24S-247 by further recrystallisation.(Found C, 57.7; H, 3.6; N, 9.6 CziHlsOaNa requires C, 57.8; H, 3.4; N,9.6%.)

I claim:

1. As new compounds, compounds of the general formula where R is agroupingselected from the group consisting of groupings having thefollowing formulae -COOZ, -CHzCl-hCOOZ,

Where Z .is an alkyl vgroup -containing not more than. fourle'arbonatoms and is an acyl group, andfBff lis a vgrouping selected `from thegroup consisting of ahydroxy group an alkoxy group, a.. hydr g,en`atom,.an Aalkylgroup, anitro group, an acyloxy group,awcarloalkoxyvgroup and an acylamino group.

2. 3:5-dinitro-4-(4 hydantoin.

' v3. 3:5-dinitro-4-(4fmethoxy.phenoxy)henzylhydantoin.

4. L3:5-dinitro 4 (4' methoxyphenoxy) N- acetylphenylalanine ethylester.

5. L 3:5 dinitro 4 -(4'acetor;.yphenoxy) N- acetylphenylalanine ethylester.

6. L j 3 i 5-dinitro-4- (4-acetamidophenoxy) N acetylphenylalanine ethylester. l "LA process v*for` the preparation of diphenylethers Vof thegeneral formula Ifo? IlTVOz hydroxyphenoxy) benzylwhere RN is a tertiaryorganic base selected from the group consisting of aliphatic tertiaryorganic bases, tertiary organic bases having aryl and alkyl groupsattached to the basic nitrogen atom and tertiary organic bases in whichthe tertiary nitrogen atom is part of a heterocyclic ring `in which theother atoms in the ring are carbon atoms, R is a grouping selected fromthe group consisting of groupings having the following foreurenco NH NHFonzen@ o o z NHY Where Z is an alkyl group containing not more thanfour carbon atoms and Y is an Vacyl' group, R is a grouping selectedfrom the group consisting of a hydroxy group, an alkoxy group, ahydrogen atom, an alkyl group, a nitro group, an acyloxy group, acarbalkoxy group and an acylamino group and X is an anion selected fromthe `group consisting of the anions of aryl sulphonic acids and theanions of hydrochloric acid, hydrobromic acid and hydriodic acid.

8. The process dened in claim 'Z in which said reaction is carried outin a liquid medium having a dielectric constant not exceeding 25.

9. A? process for the preparation of diphenylethers of the generalformula Nonv which comprises reacting together an ester of the generalformula i NO2 a phenol of the `general formula NHY where Z is an alkylgroup containing not more than four carbon atomsv and Y is an acylgroup,

46 R is a grouping selected from the group consisting of a hydroxygroup, an alkoxy group, a hydrogen atom, an alkyl group, a nitro group,an acyloXy group, a carbalkoxy group and an acylamino group and X is theanionic portion of an aryl sulphonic acid.

10. The process defined in claim 9 in which the reaction is carried outusing in place of said ester compounds which when reacted together yieldsaid ester. i

11. The process dened in claim 9 in which the reaction is carried out ina liquid medium having a dielectric constant not exceeding 25.

12. A process for the preparation of 3:5-dinitro-a-(4'methoxyphenoxy) Nacetyl phenylalanine ethyl ester which comprises reacting thep-toluenesulphonyl ester of N-acetyldinitro-tyrosine ethyl ester, saidlast mentioned ester having the formula NHCOCHa NO2 NHY with a phenol ofthe general formu Where RN is a tertiary organic base selected from thegroup consisting of aliphatic tertiary organic bases, tertiary organicbases having alkyl and aryl groups attached to the basic nitrogen atomand tertiary organic bases in which the basic nitrogen atom is part of aheterocyclic ring in which the other atoms in the ring are carbon atoms,R" is an alkoxy group, X is the anionic portion of an aryl sulphonicacid, Y is an acyl group and Z is an alkyl group containing not morethan four carbon atoms.

15. The process defined in claim 14 in which the reaction is carried outin a liquid medium having a dielectric constant not exceeding 25.

16. The process defined in claim 14 in which the laevo isomer of saidquaternary salt is used in the reaction.

17. A process for the preparation of diphenylethers of the generalformula Ilm:

which comprises reacting a Quaternary salt of the general formula witha, phenol of the general formula where RN is a tertiary organic baseselected from the group consisting of aliphatic tertiary organic bases,tertiary organic bases having aryl and alkyl groups attached to thebasic nitrogen atom and tertiary organic bases in which the tertiarynitrogen atom is part of a heterocyclic ring in which the other atoms inthe ring are carbon atoms, R' is a grouping selected from the groupconsisting of groupings having the following formulae -COOZ,-CH2CH2COOZ,

NH Ilm N16 and oHzcHcooz REFERENCES CITED The following references areof record in the file of this patent:

UNITED STATES PATENTS Name Date Avakin July 26, 1949 OTHER REFERENCESHarington et al.: Biochem. Journal.,v vol. 21 (1929), pp. 169-183.

Number

1. AS NEW COMPOUNDS, COMPOUNDS OF THE GENERAL FORMULA